The prevalence of overweight in children and adolescents has tripled during the past 30 years, and >60% of US adults are now overweight. The alarming rise in body weight in both children and adults has likely occurred because the current environment affords easy access to calorie-dense foods and requires less voluntary energy expenditure. However, this environment leads to obesity only in those individuals whose body weight regulatory systems are not able to control body adiposity with sufficient precision in our high calorie/low activity environment, which suggests there are subgroups in the US with a uniquely high susceptibility to weight gain under the prevailing environmental conditions. Indeed, certain ethnic and racial subgroups, such as African Americans, do appear to have more difficulty matching caloric intake and energy output in this environment, predisposing them to a greater incidence of overweight and obesity. During adolescence, African American boys and girls experience a steady rise in BMI such that twice as many African American girls and boys have a BMI > 95th percentile. These differences in prevalence are not fully accounted for by socioeconomic or cultural factors. The greater adiposity of African American children and adolescents confers risks for obesity's co-morbid conditions, such as Type 2 diabetes, hypertension, and atherosclerotic cardiovascular disease. These obesity-related comorbid conditions contribute to the greater mortality found in some minority groups in the US. However, data also suggest that the predictive risk factors related to body composition and the therapeutic approaches for these comorbid conditions that are derived from the study of Caucasians may be less applicable to those of differing ethnicity or race. Effective prevention and treatment of these obesity-related disorders requires a better understanding of the key elements for body weight regulation. The research of the Unit on Growth and Obesity is directed at increasing our understanding of the metabolic and behavioral factors involved in determining body weight regulation and body composition during childhood, with a special emphasis on minority populations. The ongoing research program prospectively evaluates risk factors for the development of obesity and its complications in children and adolescents, studies the effects of the new weight loss medications on body weight and obesity-related comorbid conditions in children and adolescents, and seeks the genetic and environmental factors important for the markedly greater incidence of obesity and its comorbid conditions in some US minority populations. A second research direction examines the pathophysiology of HIV-treatment-associated lipodystrophy in children and adults. Using classical association studies, we are studying polymorphisms in genes involved in the leptin signaling pathway, to attempt to identify gene variants impacting on body composition that have differing frequency in African American and Caucasian children. Genes currently under study include proopiomelanocortin, the melanocortin receptors 3, 4, and 5, and neuropeptide Y and its receptors. Polymorphisms in the melanocortin 3 receptor that affect its function appear to be prevalent in overweight African American children. In addition, we have studied genes important for energy expenditure, such as the mitochondrial uncoupling proteins. We have found that alterations in the POMC sequence are more prevalent in African American children, but are not associated with excess body weight in African American and Caucasian children. Because in Caucasians, amount of visceral fat is highly associated with the complications of obesity, we have studied the distribution of adipose tissue in African American and Caucasian children. We have found that there is less visceral abdominal adipose tissue in non-obese and obese African American children than Caucasian children, but considerably greater insulin resistance in African American children, assessed through hyperglycemic and euglycemic clamp studies. These results imply the relationship between visceral fat and the complications of obesity are different in African Americans and Caucasians. The susceptibility to weight gain in African American may also result from differences in metabolic efficiency: we have also found that resting energy expenditure is approximately 90 kcal/d less in African American than in Caucasian normal weight and overweight boys and girls. Our studies suggest that these differences are not explained by difference in the hormone leptin. In ongoing protocols, we are studying normal weight African American and Caucasian children and adolescents, African American and Caucasian children who are already obese, and the non-obese African American and Caucasian children of obese parents, in order to determine if racial differences in body composition, metabolic rate, insulin sensitivity, glucose disposal, or genetic factors believed to regulate metabolic rate, such as the uncoupling proteins, leptin and its receptor, and the beta-3 adrenergic receptor, exist prior to puberty. Psychological and behavioral factors, such as propensity to engage in binge eating behavior, are also examined. We have found that 6-11 year old children endorsing binge eating behaviors have greater adiposity than those who never report binge eating behaviors. Children are being studied longitudinally into adulthood. We hypothesize that differences in these factors will predict the development of obesity in the populations studied, and may be of great importance in developing rational approaches for the prevention and treatment of obesity in the diverse US population. Given the rapid increase in the prevalence of obesity, the development of treatments for obesity in childhood is urgently needed. In two ongoing clinical protocols, we are studying novel approaches to the control of body weight in children. We have completed a pilot study demonstrating that severely overweight adolescents can lose weight when enrolled in a comprehensive weight management program which includes the novel gastrointestinal lipase inhibitor, orlistat, as an adjunct to a behavioral modification program. We have also found evidence that one mechanism through which orlistat may affect body weight is by changing the hedonic value of dietary fat. A randomized trial using orlistat is currently underway. A second study examines the mechanism by which another novel weight loss agent, metformin, may affect the body weight of younger children who have hyperinsulinemia. A third randomized controlled trial examines the role of supplemental dietary calcium for body weight regulation in adults. The UGO also studies HIV-treatment-associated lipodystrophy. HIV-infected children and adults, particularly those treated with protease inhibitors, often develop a lipodystrophy that includes significant changes in body shape, with fat loss in the face, arms and legs, and fat gain in the trunk. This lipodystrophy is often accompanied by hypertriglyceridemia, hypercholesterolemia, and hyperinsulinemia. Understanding the pathophysiology of lipodystrophy is therefore important for the long-term therapy of HIV infection. We have studied the etiology of HIV-associated lipodystrophy in clinical populations. We reported that visceral adipose tissue is increased in HIV-infected adults, and have found marked abnormalities in both insulin sensitivity and control of cholesterol and triglyceride metabolism, and have examined the metabolic consequences of interrupting HAART. Subsequent studies have ruled out alterations in the hypothalamic- pituitary-adrenal axis as causative in this syndrome. Ongoing studies attempt to elucidate the alterations in adipocyte function that arise as a result of exposure to the components of HAART.